52 Review

DOI: 10.4274/tjem.2017-56531
Turk J Endocrinol Metab 2017;21:52-59

Genetics of Type 2 Diabetes Mellitus-Asian Perspective

(A Review)
Tip 2 Diabetes Mellitusun GenetiiAsya Perspekti
(Bir Gzden Geirme)

* Baqai Medical University, Karachi, Pakistan

** Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has come up as a major cause of mortality and continues to cause enormous
socio-economic loss across the globe. In the purview of this, a thorough understanding of the pathophysiology, etiology, and pathogene-
sis of the condition is the need-of-the-hour so as to develop potent therapeutics to have a better control of T2DM. In the developing co-
untries, especially the South Asian region, the condition has become a major health issue owing to the low income and distinct
socio-economic patterns. In the European population, a variety of genes have been found to be associated with T2DM; however, their
contribution to the other ethnic groups is still unclear. In recent years, various research groups analyzed the prevalence of such genes in
Asian populations. The Genome Wide Association Scan (GWAS) successfully identied more than 70 genetic variants that are associated
with the T2DM. The present article intends to provide a comprehensive account of the major studies on the genetics of T2DM, with spe-
cial reference to the Asian population. The various risk factors and the complications associated with the T2DM will be discussed. The re-
view also highlights the major differences and similarities between the susceptibility loci that have been investigated in different ethnicities
to provide a novel insight into the disease pathogenesis and its heritability patterns. The information presented, herein, on the genetics of
type 2 Diabetes Mellitus holds signicance as it paves the way for the development of potential biomarkers and strengthens the fact that
specic genetic alterations have important functional roles in the progression or development of T2DM.
Keywords: Diabetes; genetics; genome-wide association scan

Tip 2 diabetes mellitus (T2DM), dnya genelinde mortalitenin majr nedeni olan bir metabolik bozukluktur. Hastaln patozyolojisini, eti-
yolojisini ve patogenezini daha iyi anlamak iin, uygun ekilde odaklanm teraptik ve aratrma abalar gereklidir; nk hastaln pre-
valans dnya genelinde yaamlar ve ekonomileri etkilemektedir. Gelimekte olan lkelerde zellikle Gney Asya blgesinde, dk gelir
ve farkl sosyoekonomik paternlere bal olarak merkezi bir salk yk olmaya balamaktadr. Avrupallar arasnda gen eitlilii T2DM
ile ilikilidir, fakat bu genetik varyantlarn dier etnik gruplardaki katklar hl ak deildir. Asyallarda yaplan eitli yeni almalar bu gen-
lerin bazlarn oaltmtr. Genom Wide Association Scan (GWAS), T2DM ile ilikili 70ten fazla genetik varyant baarl bir ekilde ta-
nmlamtr. Metodoloji, zellikle Asya lkelerinde T2DMnin genetiiyle ilikili literatr aratrmasn iermitir. Bu gzden geirme T2DM,
risk faktrleri ve komplikasyonlaryla ilikili majr genetik tabanl almalarn ksa bir zetidir. Ayrca, farkl etnisitelerde aratrlan duyar-
llk loksnun majr fakllklarn ve benzerliklerini vurgulamaktadr ki bu da patogenez ve kaltm mekanizmalarna yeni bir bak as sa-
lamaktadr. T2DMnin genetiinin ortaya karlmasndaki bu ilerlemeler, potansiyel biyomarkerlarn gelitirilmesinde ve spesik genetik
bozukluklarn fonksiyonel rolnn ortadan kaldrlmasnda byk neme sahiptir.
Anahtar kelimeler: Diyabet; genetik; tm genom balant analizi

Introduction
Diabetes is a prolonged chronic metabolic disorder that has been
regarded as the seventh leading cause of death (1). It is expected
that about 642 million individuals will acquire diabetes by the year
2040, as per the 2015 atlas of the International Diabetes Federation
(IDF). In the developing countries, like, Pakistan, which has a pop-
ulation of 161.66 million, an estimated 6.7 million people get af-
fected with the condition according to the IDF; this figure is
predicted to increase up to 12.8 million by the year 2035 (1, 2). The

Address for Correspondence: Asher Fawwad PhD, Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan.
Phone: 92 21 36707179 E-mail: research@bide.edu.pk Received: 23/07/2016 Accepted: 09/12/2016
Copyright 2017 by Turkish Journal of Endocrinology and Metabolism Association
Turkish Journal of Endocrinology and Metabolism published by Trkiye Klinikleri.
Turk J Endocrinol Metab
2017;21:52-59
Diabetic Association of Pakistan (DAP) has been involved in con-
ducting national surveys on diabetes and has contributed signifi-
cantly as the WHO collaborating center for diabetes (3-7).
The rapid increase in the prevalence of diabetes is mainly due to
the environmental and behavioral changes that may have resulted
from the lifestyle changes. The high rates of urbanization have
been recorded for Korea, Malaysia, Singapore, Philippines, and In-
donesia, while India, Pakistan, China, and Thailand display inter-
mediate rates followed by Sri Lanka and Bangladesh, where
urbanization has been slow. Although, diabetes is caused by var-
ious factors, however, a sedentary lifestyle remains the major
cause. There has been a high incidence of obesity along with dia-
betes among obese children and women, especially from the
South Asian countries. It has been reported that certain genetic fac-
tors are responsible for predisposition of South Asians to diabetes,
as confirmed from the data on immigrant Pakistani population that
demonstrates the association of certain genetic variants with type
2 diabetes (8). Further, an enormously high rate of chronic compli-
cations has been linked to diabetes as the latter affects every organ
of the afflicted human body, causing chronic diseases, such as
retinopathy, neuropathy, nephropathy, and stroke. The situation
gets further complicated by the rising prevalence of metabolic syn-
drome (MS), childhood obesity, and the younger ages of the onset
of type 2 diabetes, which is a common occurrence in the develop-
ing world, especially, in the South Asian countries.
In view of this, the present review discusses the relevant studies
that have been conducted on the Asian population, in order to
highlight the genetic basis of the manifestation of the type 2 DM.
Methodology
At first, information was extracted from the evidence-based re-
search studies on genetics of type 2 diabetes followed by a spe-
cific focus on the genetics of type 2 diabetes in Asia. The strategies
that were employed to search and retrieve the required informa-
tion are given below:
A. Retrieval of research evidence on genetics of type 2
diabetes
Database searched for medical research articles
The search for basic research studies on genetics of T2D in Asia
was initiated by searching the medical research articles indexed in
PubMed. It is managed by the National Library of Medicine (NLM)
of the US National Institutes of Health and is the worlds largest
medical library. PubMed comprises more than 20 million citations
for biomedical literature from MEDLINE, life science journals and
books that are available online.
Use of citation manager for searching articles
For searching, storing, and sorting the articles, the citation man-
ager software, called the Reference Manger was used. The soft-
ware was also utilized for citation of the articles in the manuscript
form.
Method of retrieving research abstracts from MEDLINE
First and foremost, the abstracts were retrieved from MEDLINE by
using the two key words: genetics and type 2 diabetes, together
using the Booleans logic operator. The retrieval of all the articles
Fawwad et al.
Genetics of Type 2 Diabetes
53
having any of the two terms was ensured by using and in be-
tween the terms. In this way, 19105 articles, which were related to
genetics of type 2 diabetes, were obtained. Another set of articles
was retrieved on genetics of type 2 diabetes in Asia; these articles
were screened to specifically suit the purpose for writing this re-
view.
Screening of the retrieved articles
The retrieved 19105 articles were screened for the selection of the
articles wherein information about genetics of type 2 diabetes was
provided. About 1669 articles were filtered that contained data on
genetics of type 2 diabetes in Asia. The articles that presented
studies on Asian immigrants were also included. The studies,
which demonstrated investigations on diabetes in context to other
diseases or testing of nutraceuticals or medicines, were excluded.
Further, efforts were made to have access to full texts of as many
articles as possible.
To include the recent updates on genetic analyses of type 2 dia-
betes, information from the relevant websites and reports were re-
trieved by searching for the basic keywords, diabetes and Asia
(along with other specific terms) using Google.
Advancement in Genetics of Type 2 Diabetes
The occurrence of T2DM genetic variants differs in various popula-
tions and ethnic groups. The identification of these variants among
diverse populations has revealed important findings that have con-
tributed toward a better understanding of T2DM at the cellular
level. The linkage analysis, candidate gene approach, large-scale
association studies, and GWAS have identified more than 70 loci
that confer susceptibility to T2DM. Of these, 45 loci were identified
in European populations and the other 29 loci were identified in
Asian populations, especially, in East and South Asians (Table 1).
In order to better understand the pathophysiology of T2DM, im-
mediate benefits were derived from these findings.
Genome Wide Association Scan (GWAS)
The two main approaches to understanding such genes are the
candidate gene approach and GWAS; however, the latter, which is
able to simultaneously scan several loci in any population, is less
expensive and less error-prone (9). GWAS revealed the associa-
tion of multiple loci with T2DM in geographically different popula-
tions, such as Americans, Caucasians, Australians, West Africans
and Europeans (10-14).
The GWAS studies, on a larger scale, have helped us to investigate
the genetic basis of the disease and identified dozens of variants
that are associated with the T2DM. However, certain rare variants
often remain undetected due to the limitations in genotyping ar-
rays. Still, the best method to detect and identify novel genes in di-
verse populations remains the GWAS, as it provides more
elaborate information on the genetic architecture of disease patho-
physiology (15-18).
Although GWAS has greatly improved our understanding towards
the genetic basis of T2D, the current genetic risk models for T2D
cannot be applied to all populations because most of these stud-
ies have been performed in the Europeans. Only limited research
studies have been conducted in the South Asians. The discovery of
 Fawwad et al. Turk J Endocrinol Metab
54 Genetics of Type 2 Diabetes 2017;21:52-59

Table 1. Type2 diabetes susceptibility genes/loci identied in Asian region.

Reference number Gene/Locus Gene name Probable mechanism Region of gene identied
19,29,42 PPARG Peroxisome proliferative activated receptor gamma gene Insulin action European
19 KCNJ11 Potassium inwardly-rectifying channel, subfamily J, member 11 Beta cell function European/Asian
19,20,25,29 TCF7L2 Transcription factor 7 like 2 Beta cell function European/Asian
19,20 CDKAL1 CDK5 regulatory subunit associated protein 1-like 1 Beta cell function European/Asian
19,20,42 CDKN2A/B Cyclin-dependent kinase inhibitor-2A/2B Beta cell function European/Asian
19,20,29 IGF2BP2 Insulin-like growth factor 2 binding protein 2 Beta cell function European/Asian
19,20,42 HHEX/IDE Hematopoietically expressed Beta cell function European/Asian
Homeobox- insulin-degrading enzyme
19,26,28,29,42 FTO Fat mass and obesity-associated protein Obesity European/Asian
19,26,41,42 SLC30A8 Solute carrier family 30, member 8 Beta cell function European/Asian
20,23,42 KCNQ1 Potassium voltage-gated channel subfamily KQT member 1 Beta cell function European/Asian
22,40 MNTR1B Melatonin receptor type 1B Beta cell function European/Asian
49 HNF1beta Hepatocyte nuclear factor 1-beta (Transcription factor 2) Beta cell function European
37 ST6GAL1 ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 Beta cell function Asian
37 GRB14 Growth Factor Receptor-Bound Protein 14 Insulin Asian
37 HMG20A High mobility protein 20 A Unknown Asian
37 VPS26A Vacuolar Protein Sorting 26 Homolog A Unknown Asian
37 HNF4A Hepatocyte Nuclear Factor 4, Alpha Beta cell function Asian
37 AP3S2 Adaptor-Related Protein Complex 3, Sigma 2 Subunit Unknown Asian
38 CDC123/CAMKID Cell division cycle 123 homolog (S. cerevisiae)/calcium/ Beta cell function Asian/European
Calmodulin dependent protein kinase ID
38 THADA Thyroid adenoma associated Beta cell function Asian/European
38 NOTCH2 Neurogenic locus notch homolog protein 2 Unknown Asian/European
38 TSPAN8/LGRS Tetraspanin8/Leucine-rich repeat containing G Beta cell function Asian/European
protein-coupled receptor 5
38,42 JAZF1 Juxta-posed with another zinc nger gene 1 Beta cell function European/Asian
38 ADAMTS9 ADAM metallopeptidase with thrombospondin type 1 motif, 9 Decreased European
insulin sensitivity
40 GCKR Glucokinase regulatory protein Increased insulin Asian
resistance
40 GCK Glucokinase Beta cell function Asian
40 G6PC2 Glucose-6-phosphatase, catalytic, 2 Beta cell function Asian
41 ADCY5 Adenylate cyclase 5 Insulin action Asian
41 GLIS3 GLIS Family Zinc Finger 3 Beta cell function Asian
42 IRS1 Insulin Receptor Substrate 1 Increased insulin European/Asian
resistance
42 CHCHD9 Putative coiled-coil-helix-coiledcoil-helix domain-containing Unknown European/Asian
protein CHCHD2P9
42 DUSP9 Dual specicity phosphatase 9 Phospatase European/Asian
42 KLF14 Kruppel-Like Factor 14 Insulin action European/Asian
44,45 RAGE Receptor for Advanced Glycation End-products Insulin action Asian
44,45 PAI-1 Plasminogen activator inhibitor-1 Insulin action Asian
49 HMGA2 High Mobility Group AT-Hook 2 Transcriptional regulator African-American
49 BCL2 B-cell lymphoma-2 Beta cell function African-American
50 VPS13C/ Vacuolar Protein Sorting 13 Homolog C Beta cell function European
50 C2CD4A/B C2 Calcium-Dependent Domain Containing 4A Beta cell function European
50 ARAP1 ArfGAP with RhoGAP domain, ankyrin repeat and PH domain 1 Insulin action European
51,52 GSTMI Glutathione-S-transferase M1 Insulin action Asian
51,52 GSTP1 Glutathione S-Transferase Pi 1 Insulin action Asian
51,52 GSTT1 Glutathione S-transferase theta 1 Insulin action Asian
54 IL-10 Interleukin 10 Insulin sensitivity Asian/Mid-Eastern
55 ARHGEF11 Rho Guanine Nucleotide Exchange Factor (GEF) 11 Insulin action Pima indians
56 SLC16A11 Solute carrier family 16 member 11 Unknown Mexican/American
Turk J Endocrinol Metab
2017;21:52-59
new loci in different populations is subject to inter-population dif-
ferences in the allele frequencies and effect sizes. There is growing
evidence that the Asian-Indians are at a higher risk for T2D as com-
pared to the other populations. Over the years, multiple genes have
been successfully identified that contribute to T2D susceptibility. The
approaches used include linkage analysis, candidate gene ap-
proach, large-scale association studies, and genome-wide asso-
ciation studies (GWAS). In an attempt to minimize the T2DM
burden, a combined analysis of these loci, such as the construction
of genetic risk scores, has to be done for easier and early diagno-
sis and development of preventive strategies against T2DM.
Genetics of type 2 diabetes in East Asian population
As described above, the genetic studies of T2DM in European pop-
ulations have enormously contributed to our understanding of
T2DM susceptibility. However, the existing literature only provides
a partial explanation for the heritability of T2DM. It is well known
that the discrepancies exist in the allelic frequencies and the effect
size in different ethnic groups. It is, therefore, important to under-
stand whether such genetic variations are also applicable to the
other ethnic populations.
Several research groups increased the number of confirmed T2DM
susceptibility loci to nine (PPAR , KCNJ11, TCF7L2, CDKAL1,
CDKN2A/B, IGF2BP2, HHEX/IDE, FTO, and SLC30A8), all these
genes may be responsible for affecting the -cell function, except
for the PPAR and FTO, which mainly affects the insulin sensitivity
(19, 20). The studies from China, Denmark and few Asian countries
revealed that a significant association exists between CDKN2A/2B,
SLC30A8, CDKAL1 and KCNQ1 gene polymorphisms with T2DM. A
number of GWA studies identified KCNJ11 and TCF7L2 genes as the
susceptibility genes for T2DM in Japanese and Chinese popula-
tions, respectively. Similarly, previously reported genes from the Eu-
ropean population, including the IGF2BP2, HHEX, SLC30A8, CDKAL1
and CDKN2A-2B have been detected in populations of Japan,
Hong Kong and Korea, of which only CDKAL1 and CDKN2A-2B
genes show association with the T2DM in Chinese population (21).
Prokopenko and colleagues reported that the variants in MTNR1B,
influence fasting glucose levels in European population (22). Like-
wise, KCNQ1 gene has been detected in Chinese population (23);
however, IGF2BP2 was not identified as the diabetes susceptibility
loci in the latter (24). In comparison to the East Asians, the fre-
quency of genetic variation in TCF7L2 gene has been reportedly
higher in Caucasians, Africans and Indians (25). Significant but
weak association of FTO variants, on both BMI and T2DM, in East
Asian population was identified (26).
Genetics of type 2 diabetes in South Asian population
As compared to Europeans, South Asians have approximately six
times high risk of T2DM, as reported in the meta-analysis, which in-
cludes the disease-association studies (27). A study, involving ap-
proximately 41,000 Europeans, showed that the FTO gene
polymorphism has significant effects on obesity-related measures
and T2DM, as accounted by body mass index (BMI) (28). On the
contrary, only a few studies have been reported from the South
Asia to highlight the association of FTO gene variants with T2DM
and obesity. A study on Sikh population from the Northern India
observed the influence of ProAla, IGF2BP2, TCLF7L2, and FTO gene
Fawwad et al.
Genetics of Type 2 Diabetes
55
variants on adiposity and T2DM (29). Several research studies con-
firmed FTO as the T2DM susceptibility locus independent of BMI.
Further studies among the South Asian population are required to
validate these findings (30).
It has been reported that every 10/100 United Kingdom (UK) based
South Asians suffers from T2DM (31). In spite of a high prevalence
rate of T2DM in the above population, data on the genetic basis of
the diseases remains scarce in it. Investigation of genetic variants
in the TCF7L2 gene in two South Asian cohorts contributes to the re-
cent efforts in genomics that led to the investigation of potential
T2DM susceptibility loci. The two sets of the South Asian population
include residents of UK and the Western India; the SNPs investi-
gated were rs7903146 and rs12255372 (32, 33). Two recent stud-
ies reported a significant association of TCF7L2 with T2DM while
assessing the disease burden in the Indian population (33, 34).
Furthermore, two separate studies failed to show any significant
association of the Pro12Ala with T2DM in South Indian population
of Chennai or in Singapore population. ProAla polymorphism has
been reportedly protective against diabetes in Caucasians (35, 36).
A multi-centered study, which was conducted in the South Asian in-
dividuals in London, Pakistan, and Singapore, revealed the asso-
ciation of six genetic variants at various cytogenetic locations
(ST6GAL1, GRB14, HMG20A, VPS26A, HNF4 and AP3S2). Further-
more, ST6GAL1, GRB14 and HNF4A polymorphisms were also as-
sociated with impaired insulin sensitivity and altered -cell function
(37). Recently, a meta-analysis of three GWA studies identified six
loci (CDC123/CAMKID, THADA, NOTCH2, TSPAN8/LGRS, JAZF1, and
ADAMTS9) in Khatri Sikhs in relation to T2DM. The authors observed
an association of the only CDC123/CAMKID with T2DM under a
dominant model. Moreover, the effect of risk allele associated with
this gene was found to be linked with altered -cell function (38).
During T2DM, the FTO expression increases in the muscle that fur-
ther alters insulin signaling, enhances lipogenesis and ROS pro-
duction, and also induces mitochondrial dysfunction (39). Another
Indian study reported the association of MTNR1B, GCKR, GCK, and
G6PC2 gene polymorphisms with abnormal plasma glucose levels
as a risk of T2DM and the related metabolic disorders in Asian In-
dians (40).
The studies conducted on Pakistani population have predicted
association of TCF7L2 and SLC30A8, ADCY5 and GLIS3 polymor-
phisms with T2DM (41). Similarly, recent GWA study investigated
around thirty SNPs in two Punjabi populations of Mirpur, Pakistan.
The two different populations comprised residents of Azad Kash-
mir and UK. SNPs within the TCF7L2, PPARG, CDKN2A/2B, FTO,
IGF2BP2, HHEX/IDE, KCNQ1, SLC30A8, IRS1, JAZF1, CHCHD9,
DUSP9 and KLF14 genes were found to be associated with T2DM
(42).
A study conducted in Vietnam reported that the FTO genetic vari-
ants are associated with T2DM even after adjustment for age, sex,
systolic blood pressure, socioeconomic status, lifestyle factors and
obesity-related traits. As per the study, the risk associated with
each risk allele of rs 9939609, was 1.80-1.92 (43).
The variants of RAGE and PAI-1 genes have been shown to be
linked with micro- and macro-vascular complications in Cau-
casians (44, 45). Another study indicated an association of RAGE
 Fawwad et al.
56 Genetics of Type 2 Diabetes
and GFPT2 gene polymorphisms with diabetic nephropathy in In-
dian subjects (46). Similarly, the RAGE polymorphism has been re-
ported to influence diabetic nephropathy, with one of its alleles
exhibiting a protective effect against macrovascular complications
of diabetes (47). Similarly, a meta-analysis of eight studies showed
the protective effect of Pro12Ala polymorphism against retinopa-
thy. A significant association of Ala allele with retinopathy in Cau-
casians was observed; however, o significant results were
observed in association with T2DM and the other related compli-
cations. No association of the C677T polymorphism of MTHFR gene
was found in Africans, Asians, and Caucasians (48). MTHFR is a
gene that is involved in DNA methylation and synthesis along with
the regulation of folate activity. It has been reported that the mutant
homozygote and heterozygote of C677T polymorphism of MTHFR
increases plasma homocysteine that is an important factor leading
to diabetic nephropathy (DN).
Genes associated with type 2 diabetes in
non-Asian populations
With the advent of GWAS, the dissection of the genetic basis for
susceptibility to T2D has experienced major breakthroughs in the
other parts of the world as well.
Grant and colleagues reported the association of TCF7L2 gene vari-
ants with T2DM in populations of Denmark, Iceland and United
States of America (USA). Moreover, HMGA2 and BCL2 genes were
also identified as T2DM risk loci in African-Americans and the other
multi-ethnic groups, respectively. The study also analyzed the effect
of risk alleles of T2DM susceptibility loci in African-Americans, His-
panics, and Asians (49). Previously, genes including TCF7L2,
SLC30A8, VPS13C/C2CD4A/B, and ARAP1 have been reported as
T2DM susceptibility loci in ancestral Europeans (50). The associa-
tion between different genes and T2DM has been assessed by sys-
tematic reviews and meta-analysis studies. Glutathione-S-
transferase including the GSTMI, GSTT1, and GSTP1 are important
genes and their association with diabetes has been investigated in
two meta-analysis studies (51, 52). Glutathione S-transferase M1
(GSTM1) and glutathione S-transferase T1 (GSTT1) genes are poly-
morphic in humans and the null genotypes render the enzymes
inactive. Several studies assessed the associations
between GSTM1/GSTT1 null genotypes and DM risk but demon-
strated conflicting results (53), while no significant association was
found between GSTP1 and diabetes (51). Further, 1082A/G poly-
morphism of IL-10 seems to be a risk factor for T2DM in Asians, but
not in Europeans or Africans (54).
Among the candidate genes that are related to T2DM, the TCF7L2
exhibits one of the strongest genetic associations with diabetes. In
a meta-analysis study after pooling all the data of European,
African, and Asian populations, it has been revealed that
rs12255372 polymorphism of the TCF7L2 gene, significantly in-
creases the risk of T2DM. In line with such findings, a positive as-
sociation is observed between rs12255372 and rs7903146 variants
of TCF7L2 gene and T2DM in Iranian population (54).
Another study reported that 1082GG genotype of IL-10 and 174CC
genotype of IL-6 are potential risk factors for T2DM in Egyptians
(55). The findings from Pima Indian population suggested that the
Turk J Endocrinol Metab
2017;21:52-59
increased risk of type 2 diabetes was due to the variation
within ARHGEF11 gene, which is nominally associated with in-
creased insulin resistance (56). SLC16A11 is identified as a novel
candidate gene for type 2 diabetes with a possible role in triacyl-
glycerol metabolism in Mexican and Latin American population
(57). The Pro12Ala polymorphism of PPAR was recorded as a pro-
tective variant, especially in the Asian population, although the re-
sults were highly heterogeneous (58).
It should be noted that the known variants cover only a minuscule
amount of the overall estimated genetic heritability; therefore, the
complete understanding of the pathogenesis of type 2 diabetes
still requires a lot of efforts.
Conclusion
Several studies specify that diabetes is a heterogeneous disease.
For the discovery of the other genetic susceptibility loci and to fur-
ther clarify the unclear heritability pattern associated with these
complex diseases, investigators should follow the genome-wide
approaches, such as GWAS. Employing the techniques for TCF7L2
and FTO, to elucidate the underlying genetic variations, will be cru-
cial for the identification of specific targets for future therapeutic in-
terventions. The contradictory results might be due to the
generation of insufficient data; therefore, a more comprehensive
approach is suggested for GWAS on specified populations with
large sample size.
However, as the disease is multifactorial in nature, the effects of
identified genes and pathways on T2D still remain largely un-
known. The identification of prognostic and predictive biomarkers
seems crucial to understanding the pathogenesis of T2D, as well as
the novel therapeutic targets, which in turn should lead to improved
outcomes in the affected patients. In contrast to the previous stud-
ies, it has been proposed that accumulation of rare variants with
mild deleterious effects may substantially increase the relative risk
at the individual level. Indeed, with the next generation of se-
quencing technologies, rare variants may be identified. Such re-
sults, together with the known common susceptibility variants, may
increase the discriminative value of genetic risk factors and push
the limit towards a threshold that may be acceptable for clinical
utility.
Ethics
Ethical approval was taken from the Institutional Review Board (IRB)
of BIDE.
Authorship Contributions
Concept: Asher Fawwad and Abdul Basit, Design: Asher Fawwad
and Abdul Basit, Data Collection or Processing: Asher Fawwad,
Analysis or Interpretation: Asher Fawwad and Rashid Kanza, Liter-
ature Search: Rashid Kanza and Asher Fawwad, Writing: Rashid
Kanza and Asher Fawwad.
Conflict of Interest: No conflict of interest was declared by the aut-
hors.
Turk J Endocrinol Metab
2017;21:52-59
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